In recent years, hyperlipidemia and arteriosclerotic diseases resulting therefrom have been rapidly increasing due to changes into high calorie and high cholesterol-type diet with improvements in living standard, obesity, lack of exercise, aging, and the like. Because a level of low density lipoprotein (LDL) cholesterol and a triglyceride level positively correlate with incidence rate of heart diseases, conventional pharmacotherapies for hyperlipidemia and arteriosclerosis have been focused on reduction of blood lipids. Whilst, it has been revealed by many researches so far that a level of high density lipoprotein (HDL) cholesterol in plasma negatively correlates with the onset of ischemic heart diseases, and hypo-HDL-emia is considered as one of risk factors of arteriosclerosis. However, no medicament is available at present which selectively and markedly raises an HDL level, and development of such a medicament has been desired.
Cholesterol ester transfer protein (CETP) is an extremely hydrophobic protein which transfers a cholesterol ester from HDL cholesterol to LDL cholesterol, very low density lipoprotein (VLDL) cholesterol or the like, and HDL cholesterol can be increased by inhibiting the transfer by CETP.
Niacin significantly increases HDL cholesterol, but has a serious problem of resistance which reduces compliance, i.e., causes hot flash, vertigo, palpitation, and the like. Although fibrates and HMG-CoA reductase inhibitors slightly increase an HDL cholesterol level (10 to 12%), they do not sufficiently satisfy medical needs of achieving significant increase of a plasma HDL cholesterol level to delay progress of atherosclerosis. Whilst, the CETP inhibitor attains a potent increase of an HDL cholesterol level, so that the inhibitor is expected to provide degeneration of arteriosclerotic lesions to an extent which cannot be exceeded by neither fibrate nor HMG-CoA reductase inhibitors, and thus it is believed to be possible to provide prophylactic or therapeutic agents for arteriosclerosis or hyperlipidemia, which are conventionally unavailable. The CETP inhibitors attain the increase in HDL cholesterol and the decrease in LDL cholesterol or VLDL cholesterol level by a mechanism different from that of HMG-CoA reductase inhibitors, and accordingly, a combinational effect of a CETP inhibitor and a HMG-CoA reductase inhibitor can also be expected.
CETP is mainly produced in the liver and small intestine in the case of human, and CETP expressed in the small intestine is considered to be involved in lipid absorption. There is also a report aiming at achieving lipid absorption inhibitory effect by inhibiting CETP of the small intestine (Patent document 1).
Several reports have been made so far about compounds to inhibit CETP activity. For example, a thiol derivative which forms a disulfide bond by a reaction with a cysteine residue of CETP to inhibit the CETP activity has been reported (Patent document 2, Non-patent document 1). However, the thiol derivative requires a large amount of administration for expression of the action, and side reactions by formation of disulfide bond with other proteins are concerned. In addition, there is no description suggesting the compounds of the present invention.
As CETP inhibitors having a mode of action different from that of the thiol derivative, tetrahydroquinoline derivatives have been disclosed (Patent documents 3 to 5). However, these derivatives are highly liposoluble compounds, and due to low oral absorption resulting from the low water-solubility, they require a pharmaceutical means for obtaining a blood level sufficient for expression of the efficacy (Patent document 6). In addition, there is no description suggesting the compounds of the present invention.
Further, tetrahydronaphthylidine derivatives, dibenzylamine derivatives and the like are disclosed as compounds having CETP inhibitory activities (Patent documents 7 to 9). However, they are highly liposoluble compounds in the same manner as the aforementioned tetrahydroquinoline derivatives. In addition, there is no description suggesting the compounds of the present invention.
Furthermore, compounds having a benzyl(heterocyclylmethyl)amine structure are disclosed (Patent document 10). However, the compounds do not have a substituent such as a lower alkyl group on a carbon atom at the benzylic position, unlike the pyrimidine compounds of the present invention having a benzyl(heterocyclylmethyl)amine structure. There is no description suggesting the compounds of the present invention. Moreover, the compounds are found to have insufficient CETP inhibitory activity as specifically shown in test examples described later.    Patent document 1: International Patent Publication WO2006/098394    Patent document 2: Japanese Patent Unexamined Publication (Kokai) No. 11-49743    Patent document 3: International Patent Publication WO2000/17164    Patent document 4: International Patent Publication WO2000/17165    Patent document 5: International Patent Publication WO2000/17166    Patent document 6: International Patent Publication WO2003/63868    Patent document 7: International Patent Publication WO2005/095395    Patent document 8: International Patent Publication WO2004/020393    Patent document 9: International Patent Publication WO2006/056854    Patent document 10: International Patent Publication WO2006/073973    Non-patent document 1: Circulation, 105(18), 2159-2165 (2002)